The suprachiasmatic nucleus (SCN) is the endogenous clock of the body regulating circadian rhythmicity and is known to be rich in vasopressin neurons (Kalsbeek et al. 2010)1, producing and releasing vasopressin with a 24 h circadian rhythm (Schwartz et al. 1983)2. A major regulatory effect of vasopressin on circadian rhythm could not be demonstrated by the prior art. The Brattleboro rat, a rat strain naturally lacking vasopressin due to a point mutation, has no obvious defect in its circadian rhythm (Groblewski et al. 1981)3. Injection of vasopressin directly in the hamster SCN had no effect on circadian phase shift (Albers et al. 1984)4. In contrast, vasopressin may modulate the circadian clock in a more subtle way. Vasopressin deficient Brattleboro rats do not respond to a 6 h phase advance of the light-dark period, but remain synchronized to the food presentation (Murphy et al. 1998)5, in contrast to normal rats, which respond both to the new light dark rhythm and to food presentation.
More specifically, the vasopressin V1a receptor was shown to have a modulatory role on circadian behavior by studying V1a knock-out (KO) mice. V1a KO mice behave normally under a normal 12 h-12 h light-dark cycle, but in absence of light (dark-dark conditions) these mice show a gradual loss of circadian rhythm characterized by an expansion of the active period. Nevertheless they still respond normally to phase-shifts induced by brief light exposure during the dark phase (Li et al. 2009)6.
We surprisingly found that administration of a single dose of a small molecule V1a antagonist to normal mice before a 6 h phase shift (6 h advance of light phase) induces a significantly faster re-entrainment to the new light-dark cycle than vehicle treated mice. More specifically, a selective V1a antagonist.
This finding is contrary to the prior art teaching, where treatment with melatonin to accelerate re-entrainment after a phase-shift, is only effective after daily administration for 3 days after the phase advance (Dubocovich et al. 2005)7.
Poor sleep can lead to numerous health disturbances including anxiety, depression, irritability, impaired social interactions and psychomotor coordination and the like.
WO 2013/1762208 describes circadian rhythm-regulating agents which comprises an inhibitor capable of inhibiting vasopressin receptors V1a and V1b.
V1a antagonists have been described in the prior art, e.g. in EP 0382185, EP 0526348, WO 94/01113, WO 94/18975, WO 95/06035, WO 96/22292, WO 96/22293, WO 97/49707, WO 97/49708, WO 98/24430, WO 99/37637, WO 99/44613, WO 99/55340, WO 99/65525, WO 00/029405, WO 00/066117, WO 01/058880, WO 01/066109, WO 02/002531, WO 02/044179, WO 02/055514, WO 03/031407, WO 03/037901, WO 03/042181, WO 04/074291, WO 04/108138, WO 2005/039565, WO 2005/063754, WO 2006/020491, WO 2006/021213, WO 2006/051851, WO 2006/058705, WO 2006/102283, WO 2006/102308, WO 2007/006688, WO 2007/009906, WO 2007/014851, WO 2007/039438, WO 2007/077122, WO 2007/109615, WO 2008/068159, WO 2008/068183, WO 2008/068184, WO 2008/068185, WO 2008/077810, WO 2008/077811, WO 2008/080842, WO 2008/080844, WO 2008/084005, WO 2010/057795, WO 2010/060836, WO 2011/120877, WO 2011/128265, WO 2011/131596, WO 2011/134877, WO